The most widely used dosage forms for oral administration include tablets and capsules. However, such dosage forms have several disadvantages. For example, it is estimated that 50% of the population have problems swallowing tablets. In particular, it is difficult for some elderly persons to swallow tablets or capsules or to medicate children who are unable or unwilling to swallow tablets or capsules. This leads to poor or non-compliance with the treatment, and thus has a negative impact on the efficacy of the treatment. The bitter taste of many actives precludes the medication from being easily sprinkled onto food, a commonly used method of administering medications to elderly and children.
A number of methods are known for masking the taste of drugs; taste masking techniques may be divided into physical, chemical, biochemical and organoleptic methods. The technique to be adopted will depend on several factors, but primarily on the extent of bitterness of the drug to be incorporated into an oral pharmaceutical formulation. Organoleptic methods of taste-masking involve addition of a flavoring and/or sweetening agent and as such are relatively simple. However, simple addition of a taste-masking agent such as a flavoring agent or sweetener is frequently not useful by itself, unless the drug to be taste-masked is not particularly bitter. The most common masking methods, however, are based on physical means, including agglomeration, coating, and microencapsulation. Microencapsulation is essentially a process by which coatings are applied to small particles of solids, droplets of liquids or dispersions, so as to form microcapsules.
The taste masked formulation of bitter drug-containing cores should allow the complete release of the drugs in the gastrointestinal tract within a suitable time period. For example, bitter drug-containing cores incorporated into chewable tablets typically have thick coatings of mostly water-insoluble polymers, to resist fracture during tablet compression and/or during chewing and concomitant leakage of the bitter active; however, in this case a substantially complete release of the drug from such chewable tablets in the gastrointestinal tract may be achieved only after several hours from administration.
Among the drugs having a bitter taste there are the bisquinoline drugs. Bisquinoline derivatives are compounds with two quinoline groups bound by a covalent aliphatic or aromatic link. Several of these compounds have been identified as antimalarian medicaments and include hydroxypiperaquine, dichlorquinazine, 1,4-bis (7-chloro-4-quinolylamino) piperazine, piperaqine. Bisquinolines includes free form of the compound and their pharmaceutically acceptable different forms, such as salts, solvates, esters, racemic form, enantiomers, diastereomers, metabolites, prodrugs, analogues, polymorphs, hydrates, hyper-hydrate. Particularly interesting is piperaquine (PQ) and piperaquine tetraphosphate tetrahydrate phosphate (PQP). PQP is the bisquinoline, 4,4′-(1,3-propanediyldi-4,1-piperazinediyl) bis(7-chloroquinoline) phosphate hydrate (1:4:4) or 7-chloro-4-[4-[3-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]propyl]piperazin-1-yl]quinoline phosphoric acid, hydrate. Its molecular formula is: C29H32Cl2N6.4(H3PO4).4(H2O), MW: 999.56. The molecular structure is:
Any crystalline polymorphs and hydrates of PQ and PQP representing different solid state molecular forms of the same compound can be used in the present invention.
Formulating piperaquine or piperaquine phosphate in their different forms is complicated by its bitter taste. Furthermore, PQP may induce chemical reactions on chemically reactive agents; instability and decomposition or degradation of chemically sensitive active agent such as dihydroartemisinin may occur when this agent is used in combination with PQP (Chem. Med. Chem., 2007, 1448-1463). Moreover, the formulation prepared with the bisquinoline drug should be controlled and customized both when PQP is used alone and in combination with other active agent(s).